Abstract: Neurodegenerative disease will increasingly plague our society as modern medicine augments the number of people reaching their seventh, eighth, and ninth decades. These pathological processes erode the functional integrity of susceptible neural circuits. Much progress has been gained in identifying mutations and gene products that underlie these disease processes, particularly early onset Alzheimer's disease (AD) and Parkinson's disease (PD). While these findings have lead to the development of mouse models of these diseases, little is known at the systems level about how these disease genes impact the function of a specific neural circuit. We have developed an experimental approach to elucidate the actions of genes that cause neurodegenerative disease in a single mammalian neural circuit. Using mouse genetics, we expressed an AD gene exclusively in primary olfactory sensory neurons in a conditional manner. Characterization of this model uncovered a population of mouse olfactory neurons that undergo enhanced cell death and axon mistargeting in a non-cell autonomous fashion in the presence of this AD gene. In this proposal, we outline a series of studies to extend our analysis of this mouse model by employing: 1. longitudinal in vivo functional imaging using multiphoton microscopy and 2. primary olfactory neuron culture that can be adapted to high throughput screens for molecules that reverse the cell death phenotype. Hits from this screen can be rapidly tested in the mouse model by intranasal delivery to the olfactory epithelium. In addition, we propose to extend this experimental approach to genes associated with other neurodegenerative diseases such as PD. Elucidation of the actions of these disease genes at a systems level with novel functional and cellular outcomes from our neural circuit mouse model and characterizing additional neurodegenerative disease genes in this model system hopefully will contribute to the development of effective therapies. Public Health Relevance: Neurodegenerative diseases in general and Alzheimer's disease in particular have an enormous public health impact currently;the estimated annual cost to our society in the USA is greater than $100 billion. Moreover, the incidence is projected to quadruple in the next 30 years as the baby boomer generation moves into their seventh, eighth and ninth decades. The development of effective therapies and/or preventive measures for these diseases would alleviate the loss of the quality of life for individuals who suffer these tragic disorders and unburden our society of their economic impact. This project will hopefully contribute to our understanding of these diseases and to the development of efficacious therapeutic interventions.